Use of electromagnetic fields in cancer and other therapies

ABSTRACT

Methods and apparatus are described for the treatment of diseases by exposures to electromagnetic fields. Also, apparatus is described for focusing the biological effectiveness of such fields on specific cells, tissues or organs of a human or animal body.

BENEFIT OF EARLIER APPLICATION

This application is a divisional application of and claims priority toU.S. patent application Ser. No. 09/737,546, entitled “Use ofElectromagnetic Fields in Cancer and Other Therapies” filed Dec. 18,2000, which claims priority to U.S. Provisional Patent Application No.60/179,738, filed Feb. 2, 2000. The entire disclosures and contents ofthe above-identified patent applications are hereby incorporated byreference.

BRIEF DESCRIPTION OF INVENTIONS DESCRIBED AND CLAIMED HEREIN

Methods and apparatus are described and claimed for the treatment andprevention of diseases by exposures to electromagnetic (EM) fields.Also, apparatus is described and claimed for focusing the biologicaleffectiveness of such fields on specific cells, tissues or organs of ahuman or animal body.

DISCUSSION OF FIELD OF THE INVENTIONS

The inventions described herein relate to the control of heat shockproteins for the treatment of disease. The control is by application ofEM fields. The diseases include the treatment of cancer and autoimmunediseases. The inventions are related to the induction by EM fields ofthe heat shock (stress protein) response, which has been implicated in anumber of diseases. I have discovered that although short-term exposuresenhance the stress response in cells, long-term exposures have theopposite effect. I also have discovered that long-term EM fieldexposures can be used to down-regulate the normal stress response andrender cells more sensitive to damage from a secondary stress. Theability of EM fields to decrease a body's stress response makes thesefields ideal candidates for the treatment of a number of diseases.

The inventions include methods and apparatus that improve the efficacyof any cancer therapy. The inventions involve the application of EMfields, with particular exposure parameters to be described, toselectively increase biological cell sensitivity to any therapeuticagent used to destroy cancer cells (for example, ionizing radiation,chemicals, drugs, etc). These EM fields could be applied to volumes oftissue in which there are biological cells targeted for destruction by acancer therapeutic agent or agents. For example, the EM fields might beapplied to solid tumors, to organs, to regions of the body in whichcancerous cells are suspected to exist, or to the body or skin as awhole. These inventions would be used as an adjuvant to cancertherapeutic agents, facilitating or modifying the action of thoseagents. This would, for example, allow a reduced dose of a therapeuticagent to have the same effect as the usual dose; or for the usual doseto have a more potent effect.

The methods and apparatus described herein can also be used to treatautoimmune diseases, including, but not limited to, multiple sclerosis,arthritis, diabetes, and psoriasis. Autoimmune diseases are among themost insidious and difficult diseases to treat and cure, because theyturn the body's immune system against its own tissues. Expression ofstress proteins on the surface of cells (these are normally found onlyin the interior of the cell) can trigger an attack on a cell by theprimary defenders in the immune response. In normal cells the stressproteins do not appear on the surface of the cell. In diseased cellsthey can appear. In autoimmune disease such as multiple sclerosis, inabnormal or diseased cells (e.g. the cells that provide the myelinsheath around nerves), stress proteins are incorrectly processed andthus appear on the cell membrane or cell surface. This triggers thedestruction of these otherwise-normal cells by cells of the immuneresponse system. My discovery in this connection is that, under certainconditions, EM fields can down-regulate (i.e. reduce the production ofstress proteins). This translates into fewer stress proteins on the cellsurface and less destruction. Thus, appropriate EM field exposure can beused to slow the progress of autoimmune disease and, in some cases,allow for the repair of the damage caused by the disease.

The herein inventions would have a significant impact. For 1999, theestimated new invasive cancer cases in the US number 1.2 million,resulting in 563,000 deaths. In addition, new basal and squamous cellskin cancers are estimated to be another 1 million. In 1990, 8.1 millionnew cancers were estimated throughout the world, with 5.6 millionrelated deaths. In addition, autoimmune diseases afflict huge numbers ofpeople in the U.S. alone (e.g. multiple sclerosis—1,400,000;psoriasis—3,000,000; diabetes—21,000,000; arthritis—81,000,000).

Current cancer therapy is predominantly accomplished by surgery,radiation therapy and chemotherapy. Radiation therapy relies on thedeposition of ionizing radiation in the cells and the resultingcytotoxic effects. Chemotherapeutic agents include alkylating agents,anti-metabolites, anti-tumor antibiotics, plant alkaloids, hormones andhormone antagonists, and other miscellaneous agents.

There are many variables affecting any form of cancer therapy that mustbe taken into account in the art. However, a universal principle is thatthe more dose of any agent that can be delivered to a target volume, orthe more effective that dose can be made to be, the more likely a cancerwill be cured, locally controlled or delayed in its progress. Thepredominant limiting factor is the tolerance of the non-targeted ornormal tissues in the vicinity of the target region, in interveningregions, or in the body as a whole.

Methods allowing for delivery of more dose to a target volume, or forimproving its effect therein; or methods selectively sparingnon-cancerous or normal tissues, or for decreasing the effect there aresaid to improve the “therapeutic advantage” of a therapeutic agent.Using radiation therapy as an example, a typical way to express thisconcept, found in any complete text on the art, is a graph oftumor-control-probability and normal-tissue-complication-probabilityversus dose. Therapeutic advantage is related to the separation of thesecurves. Factors that increase the separation improve the therapeuticadvantage.

I have discovered that, under certain conditions, EM fields can makebiological cells and tissues more susceptible to many forms ofdeleterious stimuli. These include, but are not limited to, a number ofdeleterious stimuli deliberately applied as therapeutic agents. Thus, Ihave discovered devices and methods to apply EM fields to selectedtissue volumes in humans and animals that will improve the therapeuticadvantage of agents used in cancer and other therapies.

Throughout this application the term electromagnetic or EM field ismeant to include such fields ranging in frequency from approximately 10Hz to 5 GHz. The effects described in this application can be obtainedusing EM fields throughout this frequency region. The choice of the typeof source of EM field to be used will be determined by the simplicityand cost of application for a particular therapy.

The herein inventions would be beneficial alone or in combination withother art that uses EM fields to reduce biological cell susceptibilityto deleterious stimuli such as the cancer therapies or their sideeffects (U.S. Pat. No. 5,968,527) ('527). These methods to reducesensitivity, that is, protect cells, would be targeted to volumes ofnormal or non-cancerous tissue in which the damage caused by thetreatment is to be minimized. Thus, for example, it is expected thatexposure of the tissue volumes to the proper sequence of EM fields willallow for both the shift of the tumor-control-probability to lower doses(this application) and the shift of the normal-tissue-complicationprobability curve to higher doses ('527). That is to say, it would makethe cancerous tissue more sensitive to the toxic stimulus and make thenormal tissue less sensitive to the toxic stimulus used in the therapy.

It will be obvious to a person skilled in the art upon reading theherein description that these techniques could be applied to othermedical procedures using deleterious stimuli which are intended todestroy or modify the biological cells in a chosen volume of tissue fora reason other than cancer therapy. For example, benign growths,keloids, arterio-venous malformations, benign prostatic hyperplasia,splenomegaly, etc.

DESCRIPTION OF RELATED ART

I have earlier received U.S. Pat. Nos. 5,450,859 ('859), 5,544,665('665), 5,566,685 ('685) and the aforesaid U.S. Pat. No. 5,968,527('527). Of these, '859, '665 and '685 relate to my discovery thatharmful effects of a low frequency field (e.g., an EM field) on cellsmay be avoided by changing one or more characteristic parameters of thefield within time intervals of ten seconds or less. No. '527 relates tomy discovery that irreversible injury or mortality in a cell caused byan adverse condition may be combated by exposure to an EM field forlimited time periods. The relevance of these patents will be furtherdiscussed below.

Stress Proteins

Organisms protect themselves against harmful stimuli by activation of anumber of different cellular protection pathways. Among these is theclassical heat shock response, in which heat shock proteins (hsps) aresynthesized (Morimoto and Fodor, 1984). In 1962, Ritossa noted thatfollowing application of heat stress there was puffing activity atcertain gene loci on Drosophila polytene chromosomes, and that thisactivity was accompanied by enhanced synthesis of a specific family ofproteins (Ritossa, 1962). Subsequently, such heat shock response hasbeen shown to occur in all organisms examined. The hsps, which are aclass of stress proteins, are a family of molecular chaperones which areinduced by a variety of environmental stresses such as heat, chemicals,hypoxia (low oxygen), incorrect glucose levels, heavy metals and aminoacid analogs. Throughout this application the terms heat shock proteins(or hsp) and stress proteins shall be used interchangeably. I have foundthat EM fields ranging from as low as 20 to 30 Hz to as high as 1 GHzcan induce this cellular mechanism for protection. The stress proteinsso induced are not related to any rise in temperature caused by the EMfields. These stress proteins contribute to protection from andadaptation to cellular stress and are responsible for the repair ofdamaged proteins.

Pre-Conditioning

Activation of the heat shock stress response pathway can yieldbeneficial effects from the production of stress proteins, which arelong-lasting (effective for up to 24 hours following induction). Thisfinding has led many researchers to search for ways to harness thesebeneficial effects as a means to protect cells and tissues against theeffects of a damaging stressor. It is now generally accepted that priorexposure of a cell or tissue to a mild stressor can confer protectionagainst a subsequent lethal stressor, and induction of stress proteinsare involved (Mestril and Dillmann, 1995). This effect is known aspre-conditioning, and can be achieved by pre-exposure to the same typeof stimulus (auto-protection), or by exposure to an unrelated stimulus(cross-protection).

Cross-Protection

The concept of cross-protection has been extensively studied inischemia/reperfusion, a significant cell stress. Hyperthermia has beenused as a means of protecting cardiomyocytes against ischemia-inducedinjury (Mestril et al., 1994). Studies have shown that a prior,hyperthermic treatment of animals can result in a significantly improvedmyocardial salvage following subsequent coronary artery occlusion andreperfusion in rats (Donnelly et al., 1992), and in an isolated,perfused rabbit heart model (Walker et al., 1993). The fact thatcardiomyocytes respond to hypoxia (diminished oxygen levels) andmetabolic stress with increased hsp70 production, points to a protectiverole for heat shock proteins during ischemia/reperfusion injury (Iwakiet al., 1993).

Currie and co-workers confirmed the protective role of hsp's. They foundthat isolated perfused hearts from rats which had received a 15 minuteheat treatment at 42° C., 24 hours previously, exhibited an improvedcontractile recovery after a 30 minute period of low-flow ischemiafollowed by reperfusion as compared to hearts from non-heat treatedanimals (Currie et al., 1988). Obviously, whole body or whole organ heatstress results in many cellular changes (besides an increase in theexpression of heat shock proteins) that could be responsible for theobserved protection against ischemia. Nonetheless, recent studies haveshown that the levels of hsp's and, in particular, the amount of hsp70present, following whole body heat shock, are directly related to thedegree of myocardial protection obtained (Hutter et al., 1994).

EM Fields, Hsp's and Cross-Protection

These findings, taken with evidence that induction of the heat shockresponse can protect against UV (Tyrrell, 1996) and X-ray (O-Rourke etal., 1997) damage suggest that heat shock protein responses may play arole in protection against various forms of oxidative stress. This isintriguing, given the discovery that short (20 minute) pre-exposures to60 Hz magnetic fields could induce protection againstanoxia/re-oxygenation in a chick embryo model (Di Carlo et al., 1998; DiCarlo et al., 1999). That work was based on earlier studies done byBlank et al. (1994) which showed that 60 Hz magnetic field exposuresyielded the same patterns of protein synthesis as heat shock. Laterstudies confirmed this finding by demonstrating that fields activateheat shock factor (Goodman et al., 1994) and enhance transcription ofhsp70 (Lin et al., 1997).

The induction of the hsp70 protein by a 60 Hz magnetic field exposurewas found to be rapid, with maximum accumulation of the protein in aslittle as 40 minutes after exposure (Han et al., 1998). The same groupalso demonstrated that AP-1, AP-2, and SP-1, other stress-inducedtranscription factors were activated in response to EM field exposures.I have found that activation of HSF in chick embryos occurs within 10minutes after the start of a 60 Hz, 8 micro Tesla (μT) EM fieldexposures. This strongly supports that the anoxia protection observed iscaused by the field-enhanced activation of cellular stress responsessimilar to those seen during heat shock. This shows that EM fieldexposures induce responses similar to those caused by heat and otherstressors, and has been discussed extensively in the aforesaid U.S. Pat.Nos. '685; '665; and '859.

EM Field Exposures Induce Protection Against a Number of Stressors

I discuss below studies and data (Table 1) that show that EM fieldexposures can induce protection against a variety of stressors. Tabularresults are given as a ratio of survival seen in stimulus-exposedembryos as compared to survival in non-stimulus exposed controls (E/Cratio).

TABLE 1 Use of EM Fields and Other Stimuli to Enhance Protection AgainstDamage from Secondary Stressors First Stimulus Secondary Stressor E/C 60 Hz EM Field Hypoxia 1.83  60 Hz EM Field UV Light 1.73  60 Hz EMField X-Rays 2.20 915 MHz EM Field Hypoxia 1.61 Heat Shock Hypoxia 1.54Heat Shock High Dose X-Ray 2.32 Low Dose X-Ray High Dose X-Ray 1.88EM Field Exposures Induce Hypoxia Protection

In accord with DiCarlo, et al., 1999, Chick embryos were exposed to a 60Hz EM field for 20 minutes. Following exposure, embryos were rested forone hour and placed into hypoxia. Final mortality observations were madefollowing re-oxygenation (Table 1). Exposure to a 60 Hz EM field inducedstatistically significant protection against hypoxia. To confirm thatactivation of the heat shock pathway would also yield protection, otherembryos were heated at 43° C. and exposed to hypoxia as described above.Heating was protective, in agreement with my hypothesis that hsp's arepart of the mechanism induced by the 60 Hz EM field.

Microwave Exposures Protect Against Hypoxia

I have discovered that microwave exposures (915 MHz) can also inducehypoxia protection in chick embryos (Table 1). This protection wasstatistically significant (P<0.01). The P value is the probability thattwo results (e.g., control survival and exposed survival) might bedifferent by random chance. Traditionally, P values of less than 0.05constitute a statistically significantly difference between two numbers.

EM Field Exposures Protect Against Ultraviolet Damage

As described by DiCarlo et al., 1999, chick embryos were exposed to 60Hz, 8 μT EM fields for 20 minutes to determine if this could protectagainst damage from UV light. They were “rested” for 30 minutes prior toplacement beneath a UV light source. Embryo survival was assessed onehour after UV (Table 1). EM field exposure induced significantprotection (P<0.001) in the chick embryo against UV damage as comparedwith non-pre-exposed control embryos.

EM Field Exposures Protect Against X-Rays

Damage caused by x-rays is primarily due to the production of reactiveoxygen species. Thus, I used heat shock, low-dose x-rays, and EM fieldsto induce protection in chick embryos against damage from subsequenthigh doses of x-ray irradiation (Table 1). Protection induced againsthigh dose x-rays by each of 3 pre-conditioning stimuli is shown: heatshock; x-rays, and EM fields. For all stimuli, a significant increase inprotection is induced (P<0.05). These data reaffirm the hypothesis thatunder certain conditions EM field exposures can protect against generaloxidative stress.

TABLE 2 Hypoxia Protection Induced by EM Fields with Different On/OffIntervals (30 minutes total on time) On Time per Off Time per Cycle(mins.) Cycle (mins.) # of Cycles E/C P† Control Control 0 1 — 30 0 12.08 <0.001  5 1 6 1.68 <0.016  5 2 6 1.45 <0.06  10 5 3 1.61 <0.031 1010 3 1.73 <0.027 10 15 3 1.90 <0.016 10 20 3 1.65 <0.018In addition, I have discovered that in order to achieve protection withan EM field exposure, it is not necessary that the exposure time (aminimum of 20-30 minutes) be continuous. In other words, one must onlybe exposed to a cumulative dose of 20-30 minutes of total exposure timein order to obtain a protective response. For example, the thirtyminutes of exposure might be given in three 10-minute, or six 5-minuteexposures given over a period of 90 minutes. Data in support of thishypothesis is given in Table 2. Chick embryos were exposed to EM fields(60 Hz, 8 μT) for a total of 30 minutes of “on time”. The onlydifference between the exposures used in Table 2 are the duration of theon time intervals (5 or 10 mins) and the duration of the off timeintervals (1 or 2 mins off time for the 5 mins on time and 5, 10, 15,and 20 mins off time for the 10 mins on time). As can be seen in thetable, significant protection is induced when the EM field is oncontinuously for 30 minutes (P<0.01). However, full protection can alsobe achieved even if the fields are turned off for as long as 2 minutes(for each 5 mins on time intervals) or 20 minutes (for each 10 mins ontime intervals). This indicates that as long as the total on time ofexposure is at least 30 minutes, the EM fields can be off for as long as20 minutes at a time during the exposure period.Other Clinical Applications of EM Field Exposures

The healing of non-union bone fractures with EM fields in humans andanimals has been demonstrated (Fitzsimmons et al., 1986; McCleary etal., 1991), and the use of pulsed EM fields was approved by the Food andDrug Administration in 1979 for treatment of non-union bone fractures.EM Field exposures have also promoted accelerated wound healing (Dindaret al., 1993), and as a treatment for inflammation in wound healing(Detlavs et al., 1996).

The findings described above teach away from my discovery that EM fieldscan be used to sensitize biological cells and weaken the body's abilityto respond to stresses. I have discovered that appropriate EM fields canweaken the stress response of cells, and can be used to increase theefficacy of x-ray and other cancer treatments and for alleviating theeffects of auto-immune diseases.

EM Fields and X-Rays

There has been previous art describing possible interactions of EMfields and x-ray exposures in several systems. Nearly all of thesestudies, however, were conducted to determine if the synergisticapplication of EM field and x-rays would lead to an increased incidencein cancer. This is in contrast to my discovery that adjuvant therapiesutilizing the combination of EM field and x-ray will enhance the killingof cancer cells, not cause their initiation. Given the controversysurrounding a possible role for EM fields in the etiology of developingcancers, researchers sought to determine if EM fields alone, or if usedin conjunction with other known carcinogens such as x-ray exposures,could increase the probability of the development of tumors. In theprior art experiments described below, x-ray exposures were used toinitiate the cancer, and the EM field exposures were shown to beco-promotion agents. This teaches away from my discovery that EM fieldscan be used as anti-cancer agents.

In 1993, Svedenstal and Holmberg looked at lymphoma development in miceexposed to x-rays and pulsed magnetic fields. The x-rays were used toinitiate cancer development. EM fields were applied to the animals tosee if there was an increased incidence of lymphoma. Their findingsindicated several correlations between the ability of x-rays to inducelymphomas in the presence and absence of an EM field. This teaches awayfrom my discovery that EM fields under certain exposure conditions canbe used to help inhibit cancers. In similar studies, Myakoshi et al.(1999) and Walleczek et al. (1999) saw that exposure of Chinese hamsterovary cells to EM fields coincident with x-ray irradiation led to anenhanced rate of mutation as compared to cells exposed only to thex-ray. Again, these studies imply that EM fields can actually helpcancers to grow, not assist in their destruction as has been mydiscovery. In addition, the EM field exposures used in the Myakoshistudy were applied for more than 40 days, and both experiments used EMfield applications that were simultaneous with or following the x-rayexposure. These findings teach away from my discovery that EM fields caninhibit tumor growth when applied prior to and in conjunction with x-rayradiation.

EM Fields and Chemotherapeutic Agents

Research covering a broad range of treatment chemicals (Chang et al.,1980; Omote et al., 1990; Cadossi et al., 1991, Pasquinelli et al.,1993; and Salvatore et al., 1994) has suggested that the efficacy ofchemotherapy drugs used to treat cancer can be modified by exposure toan EM field. In these studies, comprising mouse in situ tumors, MCF-7breast cancer, leukemic and chemo-resistant cell lines, EM fields wereapplied after application of the chemotherapeutic agent This teachesaway from my invention, which demonstrates that EM field exposures willbe maximally effective in increasing cell death from chemotherapeuticswhen applied prior to application of the anti-cancer agent. In addition,in several of the studies (Omote and Chang), the strength of themagnetic field used was up to 100 times higher than those utilized in mydiscovery, and the signals used were a very special pulsed field(Cadossi and Pasquinelli) which induced electric fields 1000 timeshigher than those which I have found effective. The practicality oftheir findings is severely limited by the necessity to use very long (atleast 96 hours), continuous exposures to high magnetic fields (on theorder of 1 Gauss). These requirements, therefore, render their exposureprotocols clinically and commercially impractical. This is in contrastto my discovery that the EM fields will have their maximum effectivenesswhen applied prior to application of the chemotherapeutic drug. This, Ihave discovered, is because the EM field exposures down-regulate thelevels of heat shock proteins within the tumor cells, rendering themmore susceptible to the chemotherapeutic agent. For greater anti-tumoreffects the EM field can be applied both prior to and for several daysfollowing application of anti-cancer agents such as ionizing radiationand toxic drugs. However in all cases the most important exposure isthat which occurs prior to chemotherapy or x-radiation.

REVIEW OF TREATMENT INVENTIONS

I have discovered the following concepts: It is possible to use EMfields to induce protection against various forms of stress. Theprotection that is induced, however, is highly dependent on the dose ofthe EM field used. Short-term field exposures (ranging from 20 minutesto several hours) are protective against stress and can also reducecytokine expression which leads to swelling and inflammation.

I have also discovered that long-term prior exposures (greater than 12hours) can cause cells, tissues and organs to be more susceptible tosubsequent damage from stress. The degree of protection or increasedsusceptibility depends upon the time duration of exposure and thestrength of the applied EM field. Table 1 gives data which demonstrateshow the duration of exposure can dramatically affect hypoxia, UV lightand x-ray protection induced by EM fields. Chick embryos were exposed to60 Hz, 8 μT EM fields 1, 8, 10, 24, 48 or 96 hours, immediately prior tohypoxia or WV light. Mortality measurements were taken after the end ofhypoxia, UV light or x-ray stress. Data is expressed as the ratio ofsurvival in the exposed embryos compared to survival in the non-EMfield-exposed embryos (E/C ratio).

TABLE 3 Use of EM Fields to Alter Protection Against Hypoxia UV Lightand X-Ray Stress Ultraviolet Hypoxia Stress Light Stress X-Ray StressDuration E/C P† EC P† E/C P† 20 minutes 1.78 <0.001 1.62 <0.001 2.16<0.001  1 hour 1.8  <0.001 *** *** *** ***  8 hours 1.83 <0.001 *** ****** *** 10 hours 1.42 <0.01  *** *** *** *** 24 hours *** *** 1.36 <0.05*** *** 48 hours *** *** 0.91 0.652 *** *** 96 hours 0.7  <0.01  0.71<0.01 0.45 <0.01  ***measurement not taken

All time durations of exposure, except for 96 hours, yielded significantincreases in hypoxia protection. Following 96 hours of EM fieldexposure, however, a significant decrease in hypoxia protection wasnoted. For example, as can be seen in Table 3, the maximum protectionagainst hypoxia stress is observed between 1 to 8 hours of exposuretime. At times less than 1 or greater than 8 hours (up to 12 hours),hypoxia protection is still observed, however to a lesser extent.

With long-term EM field exposures prior to UV light stress, maximumincreased susceptibility occurs at times greater than 48 hours, althoughsome increased sensitivity and susceptibility is noted at times between12 and 48 hours. Similar results can be obtained using EM fields up tofrequencies as high as several GHz and at intensities of the order ofseveral milliwatts/cm² and higher. The table shown here clearlydemonstrate that the dose of EM fields used is critical in predictingtheir effect. It is important to note that none of the fields I haveused cause a measurable rise in the temperature of the tissue.

Significant UV protection is seen only for the 20 minute and 24 hourexposure, with significant de-protection observed for the 48 and 96 hourtime points. This led me to hypothesize that EM fields could alsodown-regulate protection against x-rays, another significant contributorto oxidative stress.

Table 3 shows how survival after x-ray irradiation of 96 hour EMfield-exposed embryos compares to embryos not exposed to EM fields. Ihave discovered that when chick embryos are exposed to a 60 Hz, 8 μT EMfield for 96 hours, the percent survival is decreased x-ray exposure. Mydiscovery that EM fields of varying frequencies and time duration canreduce the stress response capabilities of cells led to the therapeuticapplications I have found and described below.

I have also discovered that long-term, continuous microwave exposures,(e.g. 915 MHz) can down-regulate protection against subsequent anoxicstress. Embryos were exposed to microwaves for the last final 48 hoursof their incubation. Following administration of anoxia andre-oxygenation, embryos were evaluated to determine mortality. I foundthat those embryos that had been exposed to the microwave were lesscapable to deal with the insult from the subsequent anoxia (data notshown).

In addition to the ability of long-term EM field exposures (on the orderof 48 to 96 hours of exposure time) to down-regulate the protective heatshock response, I have also discovered that short-term field exposures,if repetitive over a period of several days, can accomplish the sametype of down-regulation and decrease protection against insult. Thisexposure protocol is extremely important for commercial and clinicalfeasibility of the use of EM fields to treat disease. In a series of 3separate studies, chick embryos were exposed to different EM fieldexposure intervals over a period of four days. All 60 Hz EM exposureswere done at 10 μT. At the end of the four days of incubation, embryoswere subjected to hypoxic stress. Final observations of survival ofcontrol and exposed embryos were made following the end of hypoxia. Datais shown in Table 4.

TABLE 4 Repeated Exposure to EM Fields Decrease Protection AgainstDamage from Hypoxia Stress Time Duration of Exposure (over 4 days) E/CP†  1 hour twice daily 0.65 <0.008 30 minutes twice daily 0.52 <0.017 30minutes once daily 0.69 <0.08 

As can be seen in the table, all three exposure regimens were effectivein lowering the hypoxia protection of those embryos which had beenexposed to the EM fields (E/C ratios less than 1 indicate a decreasedsurvival in EM-exposed embryos as compared to controls). The greatestpercent decrease in protection was noted for the 30 minutes, twice dailyexposure condition (48%). The other regimens showed an approximate 34%decrease in hypoxia protection as compared to sham-exposed controls.Clearly, the repetitive nature of the EM field exposures are somehowdecreasing the ability of the embryos to protect themselves against thepotentially-lethal hypoxic stress. Similar patterns of decreased hypoxiaprotection are observed when EM field exposures are maintainedcontinuously throughout the 4 day incubation period.

In considering the results presented in Tables 2 and 4 above, it will beseen that 30 minute exposures given each day over a period of severaldays will down-regulate protection against hypoxia even if the 30 minuteexposures are not continuous. I have discovered that down regulationstill occurs if cumulative 30 minute exposures are given repeatedly,once or twice daily over a period of several days. By cumulative I meanthat even if the exposures are interrupted for several (e.g. up to 20)minutes they still induce down regulation if given repeatedly overseveral days. I also have discovered that the continued exposure oncedaily to the EM field after the stress treatment will continue toenhance effectiveness.

My inventions should be very useful in chemotherapy. The application ofmy special electromagnetic fields to tumor cells will make them moresusceptible to subsequent treatments using toxic chemicals. For example,taxol is used in chemotherapy because it hinders the growth process oftumor cells. I have investigated the effect of EM fields on the abilityof taxol to create abnormalities in rapidly dividing cells. The modelfor this purpose was chick embryos. The embryos were incubated in thepresence of a 60 Hz, 8 μT EM field. After 48 hours of continuousincubation, either dimethyl sulfoxide (DMSO) alone (controls) or Taxoldissolved in DMSO was injected. EM field incubation was continued for anadditional 48 hours. At the end of 4 days incubation, embryos werevisualized and classified as normal or abnormal (deformed, young, ordead). The results are shown in Table 5.

TABLE 5 Effect of EM Field Exposures on Taxol-Induced Abnormalities inChick Embryos Treatment Percent Abnormal Embryos Taxol Alone 19.3Taxol + EM Fields 31.1

It can be seen from Table 5 that the exposure to EM fields beginningprior to introduction of the taxol incubation of embryos with taxol inan EM field leads to a very significant increase in the toxic effect ofthe taxol. Although in this example the EM field stays on after thetaxol has been injected I have found that similar effects can beobtained even if the field is turned off prior to administration of thetaxol. Thus, I have discovered that long-term exposure to EM fields canlead to a down-regulation of the biological cell's ability to respondto, and thereby protect against a chemotherapeutic agent. This increasein sensitivity to toxic agents can be achieved with fields ranging infrequency from as low as 30 Hz to as high as 1 GHz. The type of field tobe used will be determined by cost of equipment and ease of application.

It will be obvious to a person skilled in the art upon reading thisapplication that this technique could be applied to other medicalprocedures using deleterious stimuli which are intended to destroy ormodify a chosen volume of tissue or biological cells for a reason otherthan cancer therapy. Some examples of this are benign growths, keloids,arterio-venous malformations, benign prostatic hyperplasia,splenomegaly, etc. Further, the adjuvant application of this techniqueis not only for treatment intended to cure, but could also be to aid inpalliative measures, for example, with ionizing radiation used forreducing the mass or growth of a tumor to temporarily relieve symptomscaused by that mass.

In regard to auto-immune diseases, these are difficult to treat and curebecause they turn the body's immune system against its own tissues. Theprimary defenders in the immune response are the cytotoxic T cells andthe antibody-secreting B cells. T cells are “programmed” to destroy anycells showing abnormal proteins on their surface. For the purposes here,abnormal refers to any protein that is not normally displayed on thecell. They are also targeted to objects coated with antibodies. Inautoimmune diseases, B cells make antibodies, which erroneously attachto self tissues and trigger their destruction by the T cells. Surfaceexpression of stress proteins (normally found only in the interior ofcells) has also been linked to the autoimmune diseases detailed below.Studies have shown that only diseased cells, not normal cells, can bemade to express stress proteins on their cell surfaces. Both heating andtreatment with toxic chemicals have been shown to cause this phenomenon.This is of significance, because heat shock proteins have been shown tofunction as immune modulators, providing a target for cytotoxic T cells.When the T cells detect a cell with stress proteins on the surface, theyare then activated to destroy the cell even when the cell is normallyfunctioning and much needed.

I have found that I can control this immune over-response through theuse of specific EM field exposures. I can down-regulate the heat shockprotein response with repeated exposures to EM fields, leading to adecreased surface expression of heat shock proteins, and a loweredimmune response against the abnormal surface marker. This downregulation will slow the progress of the autoimmune disease, and/orminimize the discomfort. In each of the autoimmune diseases describedbelow, it is obvious to someone skilled in the art that the unwantedappearance of surface stress proteins is a factor both in theprogression of and the pain and discomfort caused by the disease. Forthe adjuvant use of EM fields with anti-cancer therapies as well as inminimizing discomfort from auto-immune diseases, down-regulation of theheat shock responses is the method of choice.

A typical application using an EM field to down-regulate stress proteinsin patients suffering from auto-immune disease would be the following.Apply a low frequency EM field (from 20 Hz to 60 kHz) whose fieldstrength is above 20 μT. For down-regulating the stress response, the EMfield exposure should given as repeated exposures (for optimal effect,at least 1 hour, twice daily (at a minimum of 10 hour interval betweenthe two exposures on any given day). These twice daily exposures shouldbe done throughout treatment. If this exposure protocol is not practicalfor a given patient, exposures may also be done for 30 minutes twicedaily or 30 minutes once daily, since both of these treatment protocolswill also be effective. At the very least, there must be at least 30minutes of cumulative EM field exposure time (over a period of severalhours). If the EM field is in the radio frequency range the appliedradiation energy density should be greater than several milliwatts persquare cm.

In the case of Multiple Sclerosis (MS), this disease is characterized bydeterioration of the myelin surrounding nerves. Myelin is composed ofthe fatty membrane of cells, which wrap around the nerves. These cellsare called Schwann cells. The loss of myelin can cause symptoms such asfatigue, and gait difficulties. There is no known cure for this disease.However, it is possible to slow it progression and minimize symptoms.Current measures include modest exercise, and avoidance of hot climatesand stressful life events. This is because one of the major targets inMS is stress proteins. The immune system destroys the myelin of nervecells expressing stress proteins, leading to increased severity ofsymptoms (Birnbaum et al., 1997). In addition, altered expression ofhsp70 has been found in the lesions and myelin of MS patients (Aquino etal., 1997). Symptoms of MS are intensified after increases in bodytemperature from a bath, or over-exertion. Exercise is important tomaintain muscle strength, but the expression of hsps can make MS worse,by providing a marker for autoimmune attack. In some cases, the drugAvonex can alter aspects of the immune system, suppressing thedestruction of myelin. This therapy, however, can cost up to $10,000annually.

Another treatment that is currently in clinical trials and shows somepromise is the administration of taxol (the same drug used inchemotherapeutic applications). The therapy is administered once amonth, and has been shown to lower the severity of symptoms associatedwith MS. The extended presence of Taxol in the tissues down-regulatesthe stress protein response. A lowered response means that stressorswill not induce the expression of hsp on the surface of the Schwanncells, and an immune “over-response” will be avoided. The end resultwill be a decreased inflammatory response of the immune system. Thistranslates into fewer attacks on the myelin, and will lead to a decreasein disease symptoms.

The Taxol treatment, however, is risky, in that any time a drug,especially a chemotherapeutic agent, is introduced into the body, thereis the possibility of serious side effects. I have discovered that EMfield exposures can be used to down-regulate the hsp response withoutcausing additional damage, leading to the same lowered immune response.Specifically, these non-invasive EM field exposures, could also be usedto lower the expression of hsp on the surface of the myclin-producingSchwann cells. This treatment will then permit the patient to partake inexercise without triggering increased severity of symptoms. The EM fieldtreatment can be used in conjunction with drugs used to treatauto-immune disease, in order to increase their efficacy, thus allowingfor lower doses of drugs, and a consequent reduction of side effects.

Arthritis is characterized by pain, swelling, stiffness, and oftendisabling joint inflammation. In rheumatoid arthritis, the most severetype of inflammatory joint disease, the body's immune system actsagainst and damages joints and surrounding soft tissue. Evidencesuggests that this targeting of the synovial cells and fluid istriggered by an auto-immune reaction due to the presence of stressproteins in the joint (Schett et al, 1998). When the joint is beingmanipulated, as during exercise, there is a mechanical shearing stressimposed on the cells and tissue within. This mechanical stress can leadto the induction of the stress protein response through the release ofinflammatory cytokines by the damaged cells, and possibly the expressionof these stress proteins on the cell surface. In the case of rheumatoidarthritis, it is believed that the immune cells of the body detect theabnormal surface expression of stress proteins and mount an overblownprotective response. The accumulation of cells and fluids relating tothe immune response is what leads to the pain and swelling associatedwith the disease. There is no cure for most types of arthritis. However,many forms of arthritis respond to a wide range of alternativetherapies. I have discovered that by using the EM field exposuresdescribed in this application, it is possible to down-regulate stressprotein levels on the cell surface, thereby limiting the immune responseagainst synovial tissues and leading to decreased swelling of the joint.This, in turn, will increase mobility, and lessen pain.

Diabetes mellitus is a group of diseases characterized by high levels ofblood glucose resulting from defects in secretion and/or action ofinsulin, a protein responsible for enhancing the uptake of consumedsugars into cells. Diabetes can be associated with serious complicationsand premature death. People suffering from this disease must receiveinsulin from external sources in order to maintain a reasonablelifestyle. Insulin-dependent diabetes has recently been linked to stressproteins, and heat shock proteins have been suggested as the primaryantigens. In fact, a current experimental drug therapy, Bimoclomal, hasbeen shown to affect the stress protein response (Szigeti et al., 2000),and has shown promise as a potential clinical tool. In certain forms ofdiabetes, the presence of the stress proteins on the cell surface of thepancreatic islet cells (which secrete insulin) leads to theirdestruction via an auto-immune reaction. Surface expression of stressproteins has been shown to enhance removal of the pancreatic cells bythe immune system, by providing a target for the cytotoxic T cellresponse. I have discovered that long-term EM field exposure therapy candown-regulate the stress protein response in the diseased cells. Becausethe loss of these cells from the over-active immune response is aprogressive condition, lowering of the islet cell surface expression ofhsps can lead to reduced destruction. With more cells available toproduce insulin, the diabetes will be less severe and its progressionwill be slowed.

The disease known as psoriasis is characterized by scaly red patches, oreruptions of the skin. Auto-immune processes have been suggested asplaying a pathogenic role. Psoriasis is believed to occur because Tcells trigger an abnormal inflammatory response in the skin tissue.Since immune responses to infections are often directed towards hsp's,studies were initiated which showed that the skin cells of individualswith psoriasis express higher-than-normal levels of hsp's (Boehncke etal., 1994). Thus, the expression of heat shock proteins by skin cellshas been postulated to be a significant factor in the physio-pathologyof psoriasis. This is not unexpected, given that outbreaks can beexacerbated by exposure to stressful life events and heat. Taxolinjections, as discussed above, have also been shown to minimizeinflammation. In addition, a current treatment for psoriasis involvesthe once daily topical application of tazarotene, (a retinoid derivativeof Vitamin A). Prolonged exposure to retinoids (given daily) has beenshown to down-regulate expression of hsp70 (Tosi et al., 1997). This isconsistent with my invention using EM field exposure, which also worksby down-regulating expression of hsp70, to minimize the inflammation andover-immune response associated with psoriasis, either alone, or incombination with existing therapies.

OPERABILITY OF INVENTIONS

Operability is based on two principles:

1. Ability to selectively either protect or de-protect a volume oftissue depending on the parameters of the EM field exposure applied; and

2. Ability to selectively target specific volumes of tissue (i.e.focusing the effect of the field) with chosen EM field exposures toelicit the desired biological effect.

These applications are aided by methods separately used in applyingcancer therapeutic agents, which facilitate targeting these agents to atreatment volume or to cancerous cells (for example the focusing ofionizing radiation used in conjunction with the EM field exposure).

Application of EM fields activates cell signaling pathways resulting inthe production of stress proteins. These stress proteins protect thecell against deleterious stimuli. However, I have discovered thatprolonged or repetitive stimulation causes the cells to diminish ordown-regulate this stress response. This leaves the cells in a moresensitive state after EM field exposure. Therefore, any therapeuticagent applied to damage these cells will be more effective.

The working hypothesis for the mechanisms presented is not intended tobe limiting. There may be additional or different mechanisms of actionnot yet recognized which are related to the change in sensitivity of abiological cell exposed to EM fields. There may even be some cellularmechanisms that work in contrast to the overall effect being targeted.The effect being targeted is the net biological change in cellularsensitivity to a given therapy. (Borrelli et al, 1996; Fuks et al.,1994; Kang et al., 1998; Matsumoto et al., 1998; Ruiter et al., 1999;Strasser and Anderson, 1995; Trautinger et al., 1997; Watters, 1999;Walter et al, 1997; Xu et al., 1998).

An Example Using Radiation Therapy (RT):

This example uses Radiation Therapy (RT), but when properly modified forthe particular application, applies equally well to other forms ofcancer therapies. These include, but are not limited to chemotherapy,hyperthermia, tissue ablation, photo-dynamic therapy, non-thermalultrasound therapies, gene therapy, etc.

An EM field is applied to a specific volume of tumor target tissue tosensitize the cells, for example, to cause a down-regulation in theability to produce stress proteins within the cells. One of the proteinsdown regulated is the inducible form of hsp70 (hsp72). This is veryimportant in mediating apoptotic cell death after deleterious stress(e.g. radiation) to cells. A decreased ability to induce hsp72 withinthe cell increases the probability the cell will undergo apoptosis inresponse to a particular dose of radiation. Apoptosis is thought to bethe predominant form of cell death in radiation-dependent tumorregression. Therefore, down-regulating, or decreasing hsp72 in thetarget volume of cells by application of the proper EM field willincrease the probability that the cells will die from apoptosis for agiven dose of radiation. Other forms of radiation-induced damageresulting in reduction of clonogenic cells within a tumor volume will besimilarly affected. (Gordon et al., 1997; He and Fox, 1997; McMillan etal., 1998; Samali and Cotter, 1996).

Summary of Treatment Inventions

To summarize at this point, my inventions involved with treatments usingEM field exposures embrace a method of targeting and enhancingtherapeutic or palliative treatments including, without limitation,physical, chemical, radiative or gene therapies applied for thetreatment and prevention of diseases. An example of the disease iscancer, in which case the EM field treatment may be administered priorto treatment with anti-cancer agents. Also, the treatment may be appliedto any autoimmune dysfunction, in which cane the EM exposures are bestdone at least 5 days per week (preferably 7), with each exposureduration lasting a minimum of 20 minutes (preferably 1 hour). Alsoembraced is an EM field treatment which is administered both prior toand following treatment with anti-cancer agents. In an exemplary case ofthe latter, the EM field exposures are administered over a period of aminimum of 2 days both prior to and following treatment with anti-canceragents, with a minimum of 1 exposure each day, and preferably 4 days,and with each exposure duration lasting a minimum of 20 minutes, andpreferably 1 hour.

DESCRIPTION OF PREFERRED EMBODIMENTS OF APPARATUS

Specific apparatus will now be described for applying appropriate,biologically effective EM fields to a chosen volume of tissue.

To aid in these descriptions, several drawings are made part of thisapplication. A brief description of each is now given:

FIG. 1. Effects of on/off 60 Hz EM fields on hypoxia protection in chickembryos

FIG. 2. Superposition of EM fields from two coils of equal amplitudes

FIG. 3. Superposition of EM fields from two coils of unequal amplitudes

FIG. 4. EM fields of Helmholtz coils and a single coil

FIG. 5. Focusing effect of two alternately pulsing EM fields

FIG. 6. Broader focus region from two alternately pulsing EM fields

FIG. 7. General instrumentation, Example 1

FIG. 8. General instrumentation, Example 2

FIG. 9. General instrumentation, Example 3

FIG. 10. General instrumentation, Example 4

FIG. 11. Complex device, Example 1

FIG. 12. Complex device, Example 2

FIG. 13. Complex device, Example 3

FIG. 14. Complex device, Example 4

FIG. 15. Complex device, Example 5

FIG. 16. Quadrupole, Example 1

FIG. 17. Quadrupole, Example 2

FIG. 18. Quadrupole, Example 3

For external application, single or multiple coils of conducting wireconnected to a current source can be used to produce EM fields ofdesired magnitude, size, shape and location, at desired times, withinthe human or animal body. A power source and antenna can be used todirect the EM field to tissue volumes within the body.

To create a uniform EM field, a pair of circular coils can be placedoutside the body in what is known as the Helmholtz arrangement. Theplanes of the coils are parallel to each other and separated by adistance which is approximately equal to the radius of the coils. Thisuniform arrangement can be used to treat large volumes of tissue. Forexample, using the field focusing technique described below a smallregion of tissue (e.g. a tumor) can be exposed for the length of timenecessary to down regulate the stress response. Then prior to theapplication of a deleterious agent such as x-rays a larger region oftissue can be up regulated (i.e. enhanced stress proteins levels) bymuch shorter or lower doses of a non-ionizing EM field exposure. In thisway the non-tumor region can be protected against any stray ionizingradiation.

Focusing of EM Fields to Specific Tissue Volumes

In the embodiments of the inventions described herein, methods are usedwhich are more general and flexible as they pertain to a wide range oftherapeutic applications, by either catalyzing or inhibiting theresponse of the cellular defense mechanisms towards the destruction ofdiseased areas or the protection of other areas againstself-destruction. The present methods utilize a new approach tooptimizing the frequency domain of the electromagnetic fields. Theyinvolve limiting the time exposure of the patient, preferably to lessthan 30 min a session, and also the amplitude of the fields, preferablyless than 2000 μT. Furthermore, the present instrumentation designproposed to apply these low amplitude fields allows for focusing of theadjuvant effect on the diseased cells, tissues or organs, with anegligible or non-existing adjuvant effect on normal cells, tissues ororgans.

Focusing the Bio-Effect of EM Fields

Variations of suitable apparatus for focusing EM fields will come tomind to persons skilled in the art. However, it is very difficult tofocus a low frequency EM field down to regions of less than 1 cm cubed.This is particularly true if the tissue region is not near the surfaceof the body. To solve this problem I have invented and now describe amethod for focusing the biological effect (bio-effect) of an EM fieldeven when the EM field itself is not focused. It is based upon mydiscovery that an athermal EM field (i.e. one which causes no increasein tissue temperature) can cause significant biological effects (e.g.modification of heat shock protein concentrations) only if the fieldparameters (e.g. amplitude, frequency, waveform) are constant forperiods of at least several seconds. (See FIG. 1 and Litovitz U.S. Pat.No 5,968,527). For example if a constant amplitude athernal EM field(that is normally bio-effective) is turned on and off at one secondintervals it will have no biological effect. For significant bio-effectto occur the field would have to be turned on and off at intervals of atleast several seconds, preferably at intervals of greater than 10seconds (FIG. 1). See also the aforesaid U.S. Pat. Nos. '859, '665, and'685.

Thus, an athermal EM field applied to tissue which has on-off cyclesranging from approximately 0.1 second to approximately 1 to 2 secondswill have no biological effect. This EM field will have no effect on theheat shock protein activity (or any other protein) in tissue. By thesame reasoning, an athermal EM field applied to a tissue which hason-off cycles of greater than 10 seconds will yield a full biologicaleffect. In addition, I have discovered that if one superposes equalfields from 2 sources each being turned on and off at, for example, 1second intervals (which would normally not yield a biological effect)and if the on time for one source is the off time for the other source(FIG. 2), then the sum field will be bio-effective. The cell “sees” thissum field as a constant field. I have found that even if the fields arenot in the same direction a bioeffect will be induced. I have found thateffects occur even if the field direction differs by up to 90 degrees.

If the amplitude of one of the alternating fields is smaller than theother (FIG. 3) then a diminished bio-effect occurs. The magnitude of theeffect decreases linearly as the amplitude of the smaller fielddecreases. If the smaller field amplitude is below 50% of the largerfield, the biological effect goes to zero. I have further discoveredthat the induced bio-effect is down about 50% when the amplitude of thesmaller field is about 75% of the larger field.

I have discovered that when tissue is exposed to an on/off uniform fieldsuperimposed on an off/on (i.e. on when the uniform field is off)non-uniform field (i.e., a field which varies in space) there is alimited region of tissue where the superimposed fields arebio-effective. This bio-effective region is the region in which the twofields are approximately equal in amplitude, i.e., the fields are within25% of each other.

One embodiment of this focusing invention is to; a) make a Helmholtzconfiguration by placing one of the Helmholtz coils on the front and theother on the back of the body and b) to place a single smaller coilwithin and approximately in the plane of one of the Helmholtz coils. TheHelmholtz coil pair will create a uniform field that is turned on andoff every second. The single coil is also turned on and off every second(off when the Helmholtz coils are on). Thus, the single coil will createa field which decreases with the distance from it as shown in the solidline curve in FIG. 4. The single coil should have sufficient number ofturns and current flowing through it to create a greater magnetic fieldin the plane of the Helmholtz coil than that caused by the currentthrough the Helmholtz coil itself. At some point the amplitude of theuniform Helmholtz field (shown as dotted and dashed lines in FIG. 4) andthe non-uniform field due to the single coil will be roughly the same.At a distance further in to the body the field due to the small singlecoil will be less than that of the uniform field (See FIG. 4). Bycontrolling the position of the single coil within the plane of theHelmholtz coil and the current in either the single or double coilconfiguration the position within the body where the two fields areapproximately equal can be controlled. This can be seen in FIG. 6 wherea low Helmholtz field (10 μT) matches the single coil field at around 13cm into the tissue whereas a higher Helmholtz field (20 μT) matches thesingle coil field at about 9.5 cm into the tissue. I emphasize againeach of these fields is on and off approximately every second, one beingon when the other is off. The exact times that the coils are on and offare not critical as long as the time lies in the range preferably from0.1 to 2 seconds. In addition, when the peak fields of the two coils areequal in a given region of tissue, the sum of the two fields must bereasonably constant in time. This constancy requirement includesconstancy of all field parameters including frequency, waveform, andamplitude.

To be bio-effective, the percentage decrease from the larger to smallerfield must be significantly less than 50%. The bio-effectiveness of afluctuating signal as pictured in FIG. 3, decreases linearly as thesmaller signal falls to lower values. When the smaller signal isapproximately 50% of the larger, the bio-effectiveness is zero. Inpractice the EM induced bioeffect significantly decreases the resistanceof a cell to deleterious stimuli when 1) the cell is exposed to thecombined field for a period greater than 48 hours and the lower field isgreater than approximately 70% of the larger field throughout theduration of the exposure. The EM field exposure during this time periodneed not be constant, but must be repeated either once or twice a dayfor a periods of about 30 minutes or more.

The results of the concepts described above are exemplified in FIG. 5.Here the bioeffect of an EM field is focused about 9.5±1 cm into thebody. The exposure conditions described here are as follows. The singlecoil is 5 cm in radius. The number of turns and the current in it aresuch that the single coil field is equal to 20 μT at a distance of about10 cm into the tissue. The Helmholtz field is 20 μT (the higher peakHelmholtz field in FIG. 2).

If it is desired to broaden the bioeffective focus region, this can bedone in a number of ways. For example any arrangement which causes thespatially varying field to decrease less rapidly will broaden the regionin which the uniform and non-uniform fields will be reasonably close inamplitude. Upon reading this application, any one skilled in the art canthink of many ways to arrange coil systems to do this. One method forexample is to place small coils in the planes of both Helmholtz coils.These small coils should have their fields opposing each other. Theresulting field between these two small coils would drop faster thanthat of the single small coil described above. Of course the pulsingfield of the small coils is, as described above, on when the pulsingfield of the Helmholtz coils is off.

I also have discovered a more flexible way of controlling the size ofthe bioeffective focus region. The method is based upon the fact that ifa field is on for times greater than 10 seconds and then off for anapproximately equal time or less it still induces a bio-effect (FIG. 1).If, for example, one now causes the amplitude of the current in theHelmholtz coils (that are coming on and off every second) to alternatebetween two values every 20 seconds, then the peak field of theHelmholtz coils will alternate between two values every 20 seconds. Inthis case, the region where the Helmholtz field is close in value to thesingle coil field will alternate between two points in the tissue. Sinceeach region sees a relatively constant field for 20 second periods, eachregion will have bioeffects induced (i.e. stress protein production willbe affected). In FIG. 6, I have plotted the superposition of the effectsof the field values of the Helmholtz coils. In this figure the peakfield of the 1 second duration pulses of a 60 Hz Em field caused by theHelmholtz coil varies from 10 to 20 μT and back every 20 seconds. It canbe seen that the higher Helmholtz field causes a peak in bioeffect tooccur at about 9.5 cm into the tissue. The lower Helmholtz field causesa peak bioeffect to occur at about 13 cm into the tissue. The net effect(shown in FIG. 6) is that the bioeffective region is broader than thatplotted above in FIG. 5 for a constant peak Helmholtz field.

It can readily be seen that, upon reading this application, any oneskilled in the art of creating EM fields can conceive of manymodifications of this setup that will cause the two alternating on/offfields to be reasonably close in magnitude at some region within thetissue, with any degree of broadening required.

To restate the above, (1) I have described above a Helmholtz pair with asingle smaller coil in the plane of one of the coils creating aninhomogeneous field across the body (Being in the plane of the Helmholtzis not necessary for the smaller coil, however, it appears convenientfor many applications). The Helmholtz pair and the single coil areturned on alternately on time scales of about 0.1 to 2 seconds. Thecells in the tissue volume where the magnitude of the EM fields isnearly the same (within about 25%) experience a relatively unchangingfield strength, thus, the magnetic field is sensed by these cells andinduces a biological effect. The other regions receive a field thatvaries at intervals that are too short, and therefore, the cells do notsense a biologically modifying field.

(2) Another possible embodiment of this method is the same as in 1,except one can use a small coil in the plane of each coil of theHelmholtz pair. If the fields of the two small coils are phased tooppose each other this would produce a smaller region where the fieldsof the Helmholtz and smaller coils would be close in value and thereforewould produce a smaller EM field induced bioeffect region.

(3) Another embodiment would be the same as in (2) except for twoorthogonal double pairs. The use of orthogonal Helmholtz coils (with orwithout the smaller coils) has the very special advantage of inducing amore uniform electric field within organs. This is important because itis the induced electric field and not the direct EM field cellinteraction that induces the bio-effects described in this application.Two orthogonal coil systems would induce electric fields in an organwhere a single field would not. Thus, as the one second on/off fieldsalternate, for example every 10 to 20 seconds, regions of an organ notaffected by one orientation would be affected by the orthogonalorientation.

(4) The same as in (1) or (2) except that the coils can rotate around anaxis orthogonal to the axis through the center of the coils.

(5) Two orthogonal Helmholtz pairs can be used in which the electricalcurrent in one coil of each pair is adjustable relative to the currentin the other coil of the pair. This creates two approximately uniformlydecreasing fields across the body, which overlap at one point. Thispoint can be adjusted by varying the relative currents in the coils ofeach pair. Each pair is turned on alternately to produce a biologicallyundetectable field in all regions except at and near the overlap.

(6) Any of the above with specially designed coil shapes which can bechosen either physically or electrically.

Devices of Increased Complexity

The ideas presented in this application for focusing the biologicaleffect must meet the specific condition that there be a combination oftwo fields that have intensities within 25% of each other within thetargeted volume. For example, intensities of 100 and 75 would be within25% of each other. This condition is independent of the orientation orpolarization of these fields. It is known by the applicant that theorientation of the fields should be chosen for optimum biologicaleffectiveness in the targeted volume. The smaller the size of thetargeted volume, the sharper the field spatial variation needs to be.The EM field magnitudes should vary by at least 50% outside the targetedvolume.

Examples to Demonstrate the Use of the Described Apparatus and Methodsof Applying EM Field in Cancer Therapy

There are two general methods and accompanying devices for applicationof an EM field to a target volume of tissue adjuvant to radiationtherapy.

1. From the Exterior of the Body

This utilizes apparatus and methods to physically direct the appropriateEM field to the tumor target volume.

Prior to application of cancer therapy, the location of the tumor/targetvolume and the relative locations and types of normal tissues aredetermined by diagnostic imaging and other medical techniques. Usingthis information, and, perhaps, methods similar to those employed inradiation therapy planning, external (fiducial) marks can be placed onthe patient surface to provide a reference coordinate system fortargeting the tumor volume within the body. Using this, external EMfield devices can be designed and applied which target the appropriatetissue with the appropriate exposure to improve the therapeuticadvantage.

For example, an external EM field system, consisting or one or morecoils, could be designed to precisely apply EM fields with theappropriate biological effectiveness to the desired internal tissuevolumes. Coil systems used to stimulate nerve firing (Ueno and Matsuda,1993) or quadrupole (Essele and Stuchly, 1993) might be appropriate.

Device design will depend upon the location of the target in the body.For target volumes close to or on the surface (e.g., skin tumors),simple coils combined with a Helmholtz coils configuration will besufficient to induce the appropriate biological effect. The strongestmeasured fields are close to the winding of the coil with a sharpdecrease towards the coil center. Single coils present a very sharpdecrease of the induced EM field close to the coil plane. They act asdipoles. Quadrupoles can also replace the previous single coils. Aquadrupole is made by placing adjacent to each other two coils withcurrents flowing in opposite directions. The calculated EM field inducedby quadrupoles exhibits a spatial peak along an axis perpendicular tothe plane of the quadrupoles whose origin is at the crossing of thewindings. This centered peak can be utilized for my present focusingtechnology.

In order to preserve this peak and eliminate the existence of sidelobes, these windings can be partially shielded with a metal suitablefor magnetic shielding (FIGS. 16, 17, 18). A metal suitable for magneticshielding can be represented by “μ-metal,” and this representation isused hereinafter. Calculations done for this configuration show thepresence of the centered EM field peak and the absence of the sidelobes. An advantage of using quadrupoles is the ability to access deepertargets within the body of the patient. The use of one quadrupole in auniform field, however, will still be limited to a large volume. Forexample, with good shielding, using a combination of a quadrupole andHelmholtz configuration, focusing at 5 cm deep under the skin can beachieved for a volume of approximately 3 cm×7 cm×10 cm. The latterdimension can be minimized to a 3 cm×7 cm×7 cm volume by using aco-planar double quadrupole configuration with an alternating on/off EMfield of the quadrupoles, with the two quadrupoles placed at 90° fromeach other (spatial quadrature) or 3 cm×3 cm×3 cm if the quadrupoles arenot coplanar.

Focusing can also be achieved by replacing the Helmholtz coilconfiguration with a non-co-planar second quadrupole, preferably inspatial quadrature from the first quadrupole, with the only conditionthat the two symmetry axes intersect in the center of the targetedvolume. The two quadrupoles can be placed anywhere, but preferably notin close proximity to each other to limit the induced fields overlap. Amodification of the quadrupole structure can be designed with two coilsplaced on a sphere in spatial quadrature. Using shielding similar tothat for the previous quadrupole, calculations of the induced EM fieldshow that the configuration is similar to that of the co-planar doublequadrupole. This configuration will simplify the design of a focusinginstrumentation for surface and deeper diseases.

These EM field-shaping techniques described above may be combined withtime- and magnitude-dependent exposure combination techniques, detailedelsewhere in this patent application.

The concept of treatment planning will be a very importantconsideration. Computer models or treatment plans may be generated whichdetail the placement of coils on or near the outside of the body and thecharacteristics of the EM field within selected volumes of tumor targetand other normal tissues. Combining this with bioeffect data for thedifferent tissues, specific applications can be planned and implementedalong with other cancer therapies.

For long term EM field exposures a wearable coil and battery system caneasily be designed by those skilled in the art.

2. From Inside the Body

This procedure operates via body cavities (intra-cavitary) or directlyinto tissues (interstitial) via apparatus inserted specifically for EMfield or for other cancer treatment purposes.

Targeting considerations will be worked out prior to treatment intreatment planning sessions. Then, devices (e.g., specially designedcoils) could be inserted into the body volume containing the tumor, orbody volumes containing normal tissue to be spared, for directapplication of the appropriate EM field to achieve the improvement intherapeutic advantage. This could be done alone or in combination withexternal applications. Ferromagnetic materials might be used inconjunction with these applications to concentrate the magnetic fields,applied either within or outside of the body, in a chosen region

For example: A device for sensitizing colorectal tumors using rectallyinserted devices could be envisioned. In this case, the maximum fieldstrength at the surface of the coil could be directly applied to theregion of colon being treated. Or, for prostate cancer, a device couldbe designed to be inserted trans-urethrally into the prostate, near thetumor site, to stimulate greater therapeutic sensitivity within theprostate disease, while a different device could be inserted rectallyfor stimulating tissue protection of the rectal wall, a predominantlimiting normal tissue in some forms of prostate therapy (e.g.,radiation, hyperthermia).

Further Details Applying to Use of EM Fields with Radiation Therapy (RT)

A fundamental principle of RT is that the more dose that can bedelivered to a tumor, the more likely it will be cured. In order toaccomplish this, there are two fundamental techniques commonly used forapplying ionizing radiation in the clinic. Each of these will be listedand an accompanying technique for using adjuvant EM field suggested:

1. Radiation therapy takes advantage of targeting tumor volumes usingx-ray (or gamma) beams from different directions that overlappredominantly in the tumor target volume. This limits the dose to thenormal tissues between the surface of the body and the tumor to thatwhich is delivered from any one direction, while the tumor volumereceives the dose from all directions. This improves the therapeuticadvantage.

In a similar way, EM field application can be selectively applied in amanner that the magnitude and duration of the field is most appropriatefor down-regulation in the region of the tumor target volume. In thisway, the tumor region can be sensitized in preference to the normaltissue. Since a margin of normal tissue around any tumor volume (0.5-1cm) is conventionally considered to be part of the therapy region, anabrupt transition of the EM field appropriate for down-regulation tothat which is not down-regulating at the boundary of the tumor is notimperative. Note that the targeting by the x-ray fields is accurate toabout 2 mm.

2. Radiation therapy treatments are divided into multiple fractions totake advantage of the relative inability of tumor cells to repairsub-lethal radiation damage compared to normal tissue. These fractionsare normally delivered 5 days per week, although many exceptions to thisschedule exist.

The appropriate use of EM fields will therefore probably requiremultiple applications to continually sensitize or re-sensitize the tumorvolume. These applications may be in the form of EM field boosts tomaintain the down-regulation within the tumor volume, extendedre-application over weekends, or some other schedule not yet recognized.

Additionally, EM fields may be found to be beneficially applied duringthe period of response of the tumor and normal tissue cells which occursduring or between treatments to further the improvement of thetherapeutic advantage.

Chemotherapy

As described above, in a similar manner, chemicals and drugs are usedfor the purpose of destroying or modifying cancer cells for the purposeof therapy. It is expected that prior to or after the start ofchemotherapy, exposure to the proper EM field will improve the cytotoxicpotential of these drugs and possibly be synergistic with other actionsof drugs as well, such as those which might enhance the effect ofradiation.

Multi-modality Therapy

Increasing tumor cell killing with adjuvant therapies is a well-knowntechnique in the art. This is accomplished, for example in RT, by addingdrugs or other forms of treatment which kill cancer cells themselvesand/or separately or synergistically increase the cells' sensitivity toradiation.

It is envisioned that adjuvant EM field application will promote thecombined capabilities of multi-modality treatments. The down-regulationof protective mechanisms within cells tends to make them sensitive tomost if not all forms of deleterious stimuli. Therefore, EM fieldexposures would be expected to complement the application of therapiesworking together and improve the overall effect of the multipletherapies.

Significance of Blood Vessel (Endothelial) Cells within a TreatmentVolume as a Target for Sensitization

The ability of a cancer tumor to grow is highly dependent on the supplyof oxygen and nutrients provided by the blood vessels. Targeting bloodvessel cells within and around a tumor for eradication has beenrecognized to be a significant goal in cancer treatment (Korner et al.,1993; Qi et al., 1998; Martin and Fischer, 1984. Blood vessel cells areof the same general type (endothelial cells) for any tumor, suggestingthat any therapeutic improvement from application of EM field toendothelial cells would potentially be applicable in any tumor type.

In contrast, the cells from different tumors are of differenthistological types and may have different responses to the EM fieldapplications, just as they tend to be differentially responsive to allother forms of treatment. Therefore, it may be necessary that somewhatdifferent EM field intensities would be needed to most effectivelymodify different tumor cell responses. This could also be the case intreating different types of tissue and other disease states.

Targeting Normal Tissues for Protection

In addition to the presently presented EM field application forsensitizing the tumor volume, it is also possible to apply an EM fieldfor protecting normal tissues. EM exposures necessary to causeprotection are vastly different from those necessary to de-protect ormake a cell less resistant to deleterious stimuli. For example, using a60 Hz, 8 μT EM field, it requires 20 minutes of exposure to provideprotection and over 40 hours to induce a reduced resistance in certaintissues. Therefore, my present invention could be used advantageously incombination with previous art (Litovitz U.S. Pat. No. 5,968,527) whichpredicts only beneficial effects.

For example, after sensitizing the tumor volume with long term EMexposures focused as detailed above, the following could be done. TheHelmholtz coil system which was placed outside the body could beactivated to apply an EM field (8 μT) for a short time (20 min). Thiswould protect the normal tissue throughout the region of the field ofthe Helmholtz coil but would not affect the region of the tumor whosestress response system had been down-regulated by the long term EMexposure. If the x-ray beam were then applied, the normal tissue wouldbe more resistant and the tumor tissue less resistant to the damagingeffect of the x-radiation. Applying the x-ray beam from differentdirections, overlapping on the tumor, would cause the normal tissue tobe further protected in preference to the tumor. In this way, more dosecould be delivered to the tumor before the limiting tolerance of thenormal tissue was reached.

Discussion of FIGS. 7-18

FIGS. 7-18 represent instrumentation examples for focusing biologicaleffects with specific combinations of induced EM fields on spatialtargets.

How to produce low-level, alternating magnetic fields of a givenmagnitude, polarization, frequency and time dependence within a chosenspatial volume has been described above. The instrumentation is designedto produce two low-level, alternating EM fields with the same frequencyto cause a biological effect within cells and tissues. The first coilconfiguration represents the primary coils and the second coilconfiguration may be referred to as the secondary coils. When fields areapplied from both coils, for full bio-effectiveness, the magnitude ofeach field must be equal to within 25%. A second condition is that theon time for the primary coils is the off time for the secondary coils,and the off time for the primary coils is the on time for the secondarycoils.

Some designs of this instrumentation are given in the following exampleswith reference to FIGS. 7-18, showing increasing complexity ofconception and design. In the following examples, coil configurationsmay be parallel, coaxial or perpendicular. If focusing cannot beachieved for the whole target, instrumentation can be adapted forscanning the target with progressive adjustments of the focusingparameters. In the Figures, the “Focusing Area” is not intended to be anexact description of the bioeffective region. It is meant to be only anapproximate representation of that region.

Instrumentation Examples Using Regular Coils

FIG. 7—General Instrumentation, Example 1

A primary Helmholtz coil configuration (coils 10 and 12) induces amostly-uniform field between the coils. A secondary coil 14 is placed onthe same axis as the primary coils, driven to produce an EM field of thesame frequency, with a magnitude decreasing from the coil plane. Thesecondary field magnitude 16 is represented as a function of thedistance from the secondary coil and compared with the magnitude 18 ofthe uniform field induced by the Helmholtz coil configuration. Thesecondary field magnitude decreases with the distance from the secondarycoil passing through the critical values of 125% and 75% of theHelmholtz coil induced field within a specific region. This region isdefined by adjusting the intensity of the current within the secondarycoil that controls the field strength within the coil plane and thegradient of the EM field. The bio-effect will be active within thisfocus area region 20 where the target 22 should be located. The focus ofthe bio-effect is then adjustable. It can be noted that the primaryHelmholtz configuration can also be modified to provide a field gradientto sharpen the region of bio-effectiveness when intensity in the coilsare set differently.

FIG. 8—General Instrumentation, Example 2

A primary Helmholtz coil configuration (coils 10 and 12) induces amostly-uniform cylindrical field between the coils. A secondary coil 24is placed on an axis 26 perpendicular to the primary axis 28 to producean EM field of the same frequency with a magnitude decreasing from thecoil plane. The secondary field magnitude is represented with thedistance from the secondary coil and compared with the magnitude of theuniform field induced by the Helmholtz coil configuration. The secondaryfield magnitude decreases with the distance from the secondary coilpassing through the critical values of 125% and 75% of the Helmholtzcoil induced field within a specific region. This region is defined byadjusting the intensity of the current within the secondary coil thatcontrols the field strength within the coil plane and the gradient ofthe magnetic field. The bio-effect will be active within this regionwhere the target 22 should be located. The focus of the bio-effect isthen adjustable. It can be noted that the primary Helmholtzconfiguration can also be modified to provide a field gradient tosharpen the region of bio-effectiveness when intensity in the coils areset differently.

FIG. 9—General Instrumentation, Example 3

Given the information conveyed by reference characters in FIGS. 7 and 8,the legends alone in the following Figures will suffice to provide aclear understanding of the following figures. Both of the single primaryand secondary coils induce fields with the same characteristics anddecreasing strengths as the distance from the coil increases. The planeof the secondary coil is placed perpendicular to the primary coil axis.In FIG. 9, both of the primary and secondary field strengths decrease tobe within 25% from each other to induce the bio-effect within a specifictarget region. This region is defined by adjusting the intensity of theprimary coil or the intensity of the secondary coil to thus control thefield strength within the coil plane and the gradient of the EM field.The bio-effect will be active within this region where the target shouldbe located. The focus of the bio-effect is then adjustable.

FIG. 10—General Instrumentation, Example 4

As shown in FIG. 10, two Helmholtz coil configurations are placed withaxes perpendicular to form the primary and secondary settings. Theprimary setting is a classical Helmholtz configuration with a uniformfield between coils. The secondary configuration is a modified Helmholtzconfiguration where the intensity of each coil is different inducing aspatial gradient for the magnetic field between the two coils. Thespatial intersection where the strength of the secondary EM field iswithin 25% of that of the uniform primary field will be the region withthe bio-effectiveness. This region is defined by adjusting the currentintensity of one or both coils of the secondary modified Helmholtz coilconfiguration controlling the field gradient and by adjusting theprimary uniform field if necessary. The bio-effect will be active withinthis region where the target should be located. The focus of thebio-effect is then adjustable. It can be noted that the primaryHelmholtz configuration can also be modified as the secondary Helmholtzconfiguration to provide a field gradient to sharpen the region ofbio-effectiveness. In a Helmholtz configuration, the current throughboth coils is to be in the same direction around the axis of the coils.

FIG. 11—Complex Device, Example 1

Instrumentation designs of increased complexity are provided forinstrumentation exterior (FIGS. 11-14) or interior (FIG. 15) to thebody. The device of FIG. 11 utilizes the concept of FIG. 10 with twoconventional coil settings: a Helmholtz coil configuration and asecondary coil setting for focusing on the targeted volume. Coilrotation about an axis 33 and adjustments of the parameters of thesecond setting may be used to scan the targeted region. In FIG. 11 areasnumbered 30 and 32 represent” the arm openings in the patient vest, andthe triangular area 34 represents the collar opening of the patientvest. The number 36 shows a chair where the patient can sit so as to nottire the patient during the exposure. Lines 38, 40 and 42 represent thesides of the patient vest. Lines 43, 44, 46, 48, 50 and 52 represent thepants and shoes of the patient.

FIG. 12—Complex Device, Example 2

This instrumentation is more simplified than FIG. 11, utilizing theconcept of FIG. 9, with only two coils with adjustable parameters (e.g.,coil configuration and currents) to focus the bio-effect on the targetedvolume. The lines in FIG. 12 corresponding to those in FIG. 11 have thesame meanings. The lines 54 with the dots 56 at the lower ends representa guiding limiting frame for the geometric adjustments of the coils.

FIG. 13—Complex Device, Example 3

This configuration utilizes the concept of FIG. 8 with the possibledesign of a portable device such as a vest. Focusing the bio-effect isachieved by adjusting either the vertical coil setting parameters or thesingle coil parameters. The construction within circle 58 represents theconnecting closure design for the coil 24. The letter “C” represents anelectrical connector allowing the current “I” to pass along the coil.This connector can be opened mechanically to take off the vest. Twowires are connected from each side of the connector “C” towards thecircle numbered 60. The construction within 60 represents the previouslydiscussed wiring connected to a power supply with safety groundingprotection.

FIG. 14—Complex Device, Example 4, Configuration examples of focusingwith double inverted circular coils with or without conventional coils

This figure shows a set of design configurations (A, B and C) thatutilize quadrupoles such as the inverted quadrupoles used for nervestimulation as mentioned elsewhere in the present application. (Aquadrupole is a combined system of two similar coils or dipoles). Theseinverted quadrupoles are more complex than single coils as known tothose skilled in the art of producing EM fields. The field induced byquadrupoles presents a larger gradient than that induced by singlecoils. The use of quadrupoles instead of single coils will be moreefficient for focusing in smaller regions. The present configurationsare utilizing the concepts presented in FIGS. 8, 9 and 10. The focusingof the bio-effect on the targeted volume is achieved by adjustingparameters (e.g., current, or angle between the coils) of the invertedquadrupoles to produce the desired EM fields described in FIGS. 8, 9 and10.

FIG. 15—Complex Device, Example 5

This figure shows designs that utilize either inverted quadrupoles ornon-inverted quadrupoles. View A is an example of a focusing deviceusing a non-inverted eight coil configuration for internal use. Use of aferromagnetic kernel within each coil can improve the magnetic fieldintensity, reducing the probe size. View B is an example of a focusingdevice using an inverted eight coil configuration for internal use. Useof a ferromagnetic kernel within each coil can improve the magneticfield intensity, reducing the probe size. View C shows one or the otherof the devices of Views A and B mounted on endoscopic tubing, which mayalso have sensors for probe placement (optical fiber, light, otherdevice). The present configuration will utilize the concept of FIG. 9 or14. The strength of the quadrupole induced EM fields can be enhancedwith ferromagnetic kernels. This amplification can be utilized tominiaturize the devices for internal use. This device can then bemounted on an endoscopic tubing coupled with other sensors or probes(e.g. for light).

FIG. 16—Quadrupole, Example 1

This figure shows a more complex instrumentation using non-coplanarquadrupoles as a primary and secondary source configuration from theconcept of FIG. 9 or as a secondary source configuration from theconcept of FIG. 14. This figure shows complex instrumentation withquadrupole settings as a combination of primary and secondary sourceconfigurations or as a secondary source configuration. The magnitude ofthe induced field in the plane perpendicular to the axis Δ on M isrepresented. The presented quadrupoles are to be shielded with μ-metaltubing (not directly represented in the figure but shown as rectangles62). Quadrupoles #1 and #2 are in spatial quadrature and also in phasequadrature (quadrupoles are in spatial quadrature when they arespatially placed at 90° from each other and they are powered with a 90°phase shift). The figure also shows the magnitude of the EM fieldinduced by a single shielded quadrupole in the plane perpendicular tothe symmetric axis of the coil originated by the point M, the fieldmagnitude being expressed in relative units. If both quadrupoles are onat the same time, the total field will be elliptically polarized. Thesuperposition of a uniform field (FIG. 10) or a field with a gradient(FIG. 10) will then provided an intersection region where allalternating fields will be within 25% from each other to induce a fullbio-effectiveness. If the quadrupoles are alternatively on and off, onlythe fields within 25% of each other will be bio-effective and they canbe used with or without supplemental coil configurations.

FIG. 17—Quadrupole, Example 2

This figure shows complex instrumentation using co-planar quadrupoles asa primary source configuration or as a secondary source configuration.The concept is the same then for the FIG. 16. The presented quadrupolesare shielded with μ-metal tubing (not directly represented in the figurebut shown as rectangles 62). Quadrupole #1 and #2 are spatially inquadrature and also in phase quadrature. This example is a complexinstrumentation with shielded quadrupole settings as a secondary sourceconfiguration either with alternating fields or a combination of bothfields to create a circular polarized field. The magnitude of theinduced field in the plane perpendicular to the axis Δ on M isrepresented. FIG. 17 also shows the magnitude of the magnetic fieldresulting from the 25% similarity in the magnitude field induced by eachof the quadrupoles. If both quadrupoles are on at the same time theresulting field will be a circularly polarized field. The superpositionof a uniform field (FIG. 8) or a field with a gradient (FIG. 8) willprovided an intersection volume where all alternating fields will bewithin 25% from each other to induced a full bio-effectiveness. If thequadrupoles are alternatively on, only the fields within 25% of eachother will be biologically active and they can be used with or withoutsupplemental coil configurations.

FIG. 18—Quadrupole, Example 3

The figure shows a more complex instrumentation with the same concept asFIG. 17 using two coils in spatial quadrature over a sphere, shieldedwith μ-metal tubing away from the winding crossing point. This figure isan example of complex instrumentation with shielded coil settings on asphere as a secondary source configuration either with alternatingfields or a combination of both coil induced fields to create a circularpolarized field. The magnitude of the induced field in the planeperpendicular to the axis Δ on M is represented. The figure also showsthe magnitude of the induced magnetic field resulting from both coils.This configuration can substitute a quadrupole configuration as in FIG.14, 15, 16 or 17.

Summary of Apparatus Inventions

To summarize the apparatus (instrumentation) inventions disclosedherein, these embrace apparatus for establishing a plurality ofelectromagnetic (EM) fields to provide a region of bio-effectiveness ina human or animal body. Means are included to generate a first EM fieldencompassing in part a region in the body wherein the bio-effectivenessis to be achieved, and means m generate at least one additional EM fieldalso in part encompassing said region. Each of the field generatingmeans includes a means for modulating each field to be at firstmagnitude for a first period of time and at a second magnitude for afollowing period of time, with changes occurring within approximately 10second intervals. Further means are provided for controlling themodulation means to cause the magnitude of the first EM field and theadditional EM field at all times to be complimentary in respect of time.Complimentary means that the on and off times fill the total timeavailable: when one is on, the other is off. The net result is thatwithin said region the respective fields will provide a combined fieldhaving a predetermined pattern of limited differences in magnitude butoutside the region the respective fields will alternate between saidfirst and second magnitudes. Where the magnitudes have limiteddifferences, e.g., within 25% or less of each other, there will bebio-effectiveness. However, the latter will not occur when outside theregion the alteration is between said first and second magnitudes. In anexemplary case, the means for generation of the first field may be apair of Helmholtz coils. The means for generation of said additionalfield may be a single coil, or it may be another Helmholtz pair ofcoils. In all cases, the axes of the coils may be at an angle to oneanother, and the angle may be a right angle. The field generating meansfor the first EM field and the field generating means for the additionalmay differ at least to the extent that at least one of the fields willhave a magnitude distance gradient (increasing or decreasing magnitudealong the axis of the field).

My apparatus inventions may also be described as means for focusing thebiological effect on cells, tissues or organs by use of an applied EMfield which results from the superimposition of two fields each of whichis biologically ineffective when applied separately. The respectivefields will be generated from a primary source configuration producing aspatially time varying EM field and from a secondary sourceconfiguration producing a spatially uniform time varying EM field of thesame frequency and waveform as the primary source configuration. Theprimary and secondary field amplitudes are to be within 25% of beingequal only on the targeted cells, tissues and organs. With the amplitudeof each field being high in one period of time, followed by a lowamplitude in the next period of time, neither field by itself (outsidethe focus region) will be biologically effective if the chances inamplitude occur within 10 second or less. However, when both of thefields are present (in the focus region), and the high amplitudes of oneof the fields occur during the low amplitude periods of the other field,a composite field will result. This may be of constant amplitude, or mayvary up m the aforesaid 25%, and the biological effectiveness willexist. The time varying fields may be uniform (high and low periods oftime equal) or not uniform (different time periods). As aforesaid, thecycle times may be up to ten seconds, e.g., 5 seconds high and 5 secondslow, preferably 2 seconds high and two seconds low. Preferably, themagnitude of the exposure from each of the source configurations shouldbe no less than 2 microTesla and no greater than 2000 microTesla. The EMfield magnitudes preferably may correspond to a radiative energy of atleast 1.0 mW/cm squared.

My focusing apparatus may also have source configurations which comprise2 quadrupoles which provide maximum fields along the symmetry axisthereof, with the field from one quadrupole is high (on) for a maximumtime of 5 seconds (preferably 2) when the field from the otherquadrupole is low (off) for a maximum period of 5 seconds (preferably2). The quadrupoles may be coaxial. The quadrupoles may have partiallyshielded windings, which may be shielded away from the axis thereof. Thesecondary source configuration may be comprised of 2 quadrupoles inspatial and phase quadrature to provide a maximum circularly polarizedfield along the symmetry axis thereof, in which case the field is high(on) for a maximum of 5 seconds (preferably 2 seconds).

Also embraced within my inventions is apparatus for use in anti-cancertreatments, comprising means for exposing both normal and diseasedtissues to EM fields for a minimum of 20 minutes (preferably for atleast 1 hour), with the field exposure ending at a maximum of 10 hours(preferably 1 hour) prior to treatment with therapeutic agents. Themagnitude of the exposures from the EM fields is dependant on the fieldtype used, with a preferred level of no less than 2 microTesla and nogreater than 2000 microTesla. Means may be included for administeringthe EM fields in conjunction with prior focusing onto the diseasedtissue alone.

My inventions also include apparatus for exposure of EM fields totissue, which comprise means for generating circular polarized fieldsfor a minimum of 20 minutes and a maximum of 10 hours, the generatingmeans including two EM field source configurations in differentconfigurations.

Consideration of Temperatures

The procedures described in this application are not causing anytemperature changes which are biologically meaningful according to whatis presently understood. While hyperthermia can produce similar effects,the methods described herein do not rely on hyperthermia to create theeffects. The use of hyperthermia has been demonstrated to be veryunreliable and very difficult to apply, although there have been severaldecades of research and clinical trials in this area.

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1. A method of targeting and enhancing therapeutic or palliativetreatments for diseased tissues or organs including, without limitation,physical, chemical, radiative or gene therapies applied for thetreatment and prevention of diseases, which method comprises the step ofmodulating response protective elements in cells, tissues or organs withselected time exposures of electromagnetic (EM) fields havingfrequencies within a range of approximately 10 Hz to approximately 5GHz, wherein the frequencies and time exposures are selected to maintainpretreatment temperature of diseased tissues or organs, wherein time andmagnitude of the exposure are dependent on the size of the diseasedtissues or organs so as to enhance the endogenous cellular protectiveresponses of normal tissues and/or suppress the endogenous cellularprotective responses of diseased tissues.
 2. A method as in claim 1wherein the disease is cancer.
 3. A method as in claim 2 wherein the EMfield treatment is administered prior to treatment with anti-canceragents.
 4. A method as in claim 3 wherein said EM field exposures areadministered over a period of a minimum of 2 days, with a minimum of oneexposure each day, with each exposure duration lasting a minimum of 20minutes.
 5. A method as in claim 4 wherein the EM exposures areadministered over a period of 4 days.
 6. A method as in claim 4 whereineach exposure duration is 1 hour.
 7. A method as in claim 2 wherein theEM field treatment is administered both prior to and following treatmentwith anti-cancer agents.
 8. A method as in claim 7 wherein the EM fieldexposures are administered over a period of a minimum of 2 days bothprior to and following treatment with anti-cancer agents, with a minimumof 1 exposure each day, with each exposure duration lasting a minimum of20 minutes.
 9. A method as in claim 8 wherein the EM field exposures areadministered over a period of 4 days.
 10. A method as in claim 8 whereinthe duration of each exposure lasts 1 hour.
 11. A method as in claim 1wherein the disease is any autoimmune dysfunction.
 12. A method oftargeting and enhancing therapeutic or palliative treatments including,without limitation, physical, chemical, radiative or gene therapiesapplied for the treatment and prevention of diseases, which methodcomprises the step of modulating response protective elements in cells,tissues or organs with selected time exposures of electromagnetic (EM)fields having frequencies within a range of approximately 10 Hz toapproximately 5 0Hz, wherein time and magnitude of the exposure aredependent on the size of the diseased tissues or organs so as to enhancethe endogenous cellular protective responses of normal tissues and/orsuppress the endogenous cellular protective responses of diseasedtissues, wherein the disease is any autoimmune dysfunction and whereinthe EM field exposures are done at least 5 days per week, with a minimumof 1 exposure each day, with each exposure duration lasting a minimum of20 minutes.
 13. A method as in claim 12 wherein the EM field exposuresare done 7 days per week.
 14. A method as in claim 12 wherein eachexposure duration lasts 1 hour.
 15. A method of establishing a pluralityof EM fields to provide a region of bioeffectiveness in a human oranimal body, the method comprising the steps of: generating a first EMfield encompassing at least in a part a region in a human or animal bodywherein the bio-effectiveness is to be achieved, generating at least oneadditional EM field also encompassing at least in part said region,modulating the first field to cause it to be at a first magnitude for afirst period of time and at a second magnitude for a following period oftime, with changes occurring within approximately 10 second intervals,modulating the additional field to cause it to be at a first magnitudefor a first period of time and at a second magnitude for a followingperiod of time, with changes occurring within approximately 10 secondintervals, and controlling the modulations to cause the magnitude of thefirst EM field and the magnitude of the additional field at all givetimes to be complementary in respect of time, whereby within said regionthe respective fields will provide a combined field having apredetermined pattern of limited differences in magnitudes but outsidethe region the respective fields will alternate between said first andsecond magnitudes.